In what the editor of the Annals of Internal Medicine called the
first "documentary evidence that proves the existence of seeding
trials," a study in that journal's August 19 issue showed how
a clinical trial of Vioxx, called ADVANTAGE, was created not to answer
scientific questions but to market the drug and increase prescriptions.
(Kevin E Hill et al., The AD VANTAGE Seeding Trial: A Review of Internal
Documents, 149 Annals Internal Med. 251 (2008),
www.annals.org/cgi/content/full/149/4/251.)

"One of the features of a seeding trial," said Annals
editor Harold Sox in an e-mail interview, "is that its scientific
value to society at large is low relative to the risks that patients
take when they agree to participate."

The study analyzed Merck's internal and external
correspondence about ADVANTAGE in documents produced as a result of
litigation brought by plaintiffs who alleged injury resulting from the
drug. (McDarby v. Merck, 949 A.2d 223 (NJ. Super. App. Div. 2008).)
Quoting Merck employees in internal documents calling ADVANTAGE a
seeding trial and detailing its origins in the company's marketing
division, the researchers concluded that the clinical trial "was
actually a sophisticated marketing tool designed to allow optimal
'seeding' of positive experiences with Vioxx among
customers--primary care physicians--before its approval." They also
noted that this purpose was hidden from participants, investigators, and
institutional review board members.

Approved by the FDA in May 1999, two months after ADVANTAGE began,
Vioxx was withdrawn in September 2004 after another trial showed a
heightened risk of cardiovascular problems in patients taking the drug.
Subsequent reports identified results, omitted from the published
reports of ADVANTAGE and another trial, that showed similar
cardiovascular problems.

In an editorial accompanying the Annals study, Sox noted that
"seeding trials can occur only because the company does not
disclose their true purpose to anyone who could say
'no.'"

That includes not only the 600 doctors and their approximately
5,500 patients who participated in ADVANTAGE, but also Sox himself. Five
years ago, Annals published the results of ADVANTAGE, showing that Vioxx
was as effective as other medications in treating osteoarthritis and was
less likely to cause stomach problems. Although an earlier study, VIGOR,
showed similar results for treatment of rheumatoid arthritis, the Annals
editors "thought [ADVANTAGE] had a useful message that would
benefit some doctors," Sox said in an e-mail.

In his editorial, Sox noted that no one from Merck told the journal
about ADVANTAGE's true purpose. Instead, the editors learned of it
in 2006 through a doctor, David Egilman, who served as an expert for the
plaintiffs in the litigation and is a co-author of the current analysis.

Jonathan Edelman, the executive director of Merck's global
center for scientific affairs, wrote a letter in response to the Annals
editors, claiming that ADVANTAGE had a "legitimate scientific
purpose" and noting that the authors of ADVANTAGE's critique
are "paid consultants to plaintiffs' lawyers in the Vioxx
litigation against Merck."

Egilman said in an e-mail interview that no one without access to
these litigation documents could have known about ADVANTAGE's
marketing purpose. (The documents used in the study are now publicly
available at http://dida.library.ucsf.edu.)

And, he said, "if there was a possible refutation [of the
current study], Merck can use any documents it wants to make any point
it thinks it can make. It didn't make any."

Last November, Merck settled with many Vioxx litigants who had
claims of heart attacks and ischemic stroke. More recently, the Third
Circuit allowed a consolidated securities fraud class action against the
company to move forward: Judge Dolores Sloviter found that there was
sufficient evidence that Merck had continued to reassure investors that
Vioxx was safe, even as its safety was questioned by independent
researchers. (In re Merck & Co., Inc., Securities, Derivative, and
ERISA Litig., 2008 WL 4138476 (3d Cir. Sept. 9, 2008).)

Mark Lanier, a Houston attorney who represents Vioxx plaintiffs,
said the Annals study marks the medical community's formal
recognition of a practice that plaintiff lawyers have long known.

"We knew of this seeding study and made an issue of it to the
jury in Ernst, the very first Vioxx trial. Merck persisted in trying to
keep the information out of the general scientific domain, but it is now
out there for the world to see. This will not affect the settlements in
place, but it may affect future studies that have marketing as their
point-while wearing the mask of science."

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